Method for the preparation of highly pure 1-androstene derivatives

ABSTRACT

A method for preparing a 1-androstene derivative which comprises reacting a 2-iodo-androstane derivative with an oxidizing agent while maintaining the pH of the reaction mixture at a specific range gives the 1-androstene derivative with high purity and yield.

FIELD OF THE INVENTION

The present invention relates to a method for preparing highly pure1-androstene derivatives.

BACKGROUND OF THE INVENTION

As is well known, 1-androstene derivative is a compound having a doublebond between the first and the second carbons of an androstane, andrepresentative drugs having such chemical structure include finasterideand dutasteride.

Finasteride (17β-(N-tert-butylcarbamoyl)-5α-4-aza-androst-1-en-3-one),the compound of formula (II) having an androstene backbone, is known tobe effective in treating benign prostatic hyperplasia and androgenicalopecia:

Benign prostatic hyperplasia and androgenic alopecia are caused bybinding of excessive 5α-dihydrotestosterone (DHT) derived fromtestosterone to an androgen receptor. The conversion of testosteroneinto DHT is accomplished by testosterone 5α-reductase, which can beinhibited by finasteride. Such inhibition of testosterone 5α-reductaseby finasteride results in a decreased DHT concentration in plasma andcells, and thus rapid recovery of prostate and increased hair growth. Inaddition to its effectiveness to benign prostatic hyperplasia andandrogenic alopecia, finasteride has excellent drug tolerance andexhibits light, temporary side effects. Currently, finasteride is theonly orally administrable product among the two hair-growth agentsapproved by the United States Food and Drug Administration.

A process for preparing finasteride is disclosed in U.S. Pat. No.4,760,071 and Korean Patent Publication No. 1990-0001206. As show inScheme 1, the carboxylic group at the 17β-position of3-oxo-4-aza-5α-androstane-17β-carboxylic acid of formula (III) isconverted into a pyridylthioester group of formula (IV) using2,2′-pyridyldisulfide. Next, the compound of formula (IV) is reactedwith tert-butylamine to obtain 17β-tert-butylcarbamoyl compound offormula (V), followed by introducing a double bond between the first andthe second carbon atoms using bezeneselenic anhydride to obtainfinasteride of formula (II).

The above process is advantageous in that the dehydrogenation reactioncan be accomplished in one step. However, it suffers from a highproduction cost due to the usage of expensive reagents such as2,2′-pyridyldisulfide and bezeneselenic anhydride, and a poor purity,e.g., in the range of 75 to 80%, due to the production of undesiredby-products. Further, it is difficult to improve the purity of theobtained finasteride even if it undergoes such purification steps ascolumn chromatography and recrystallization.

European Patent No. 298,652, U.S. Pat. Nos. 5,084,574 and 5,116,983, andKorean Patent Publication No. 1996-0015038 disclose a process forpreparing finasteride, which comprises silylating the 3-oxo group in theabove compound of formula (III) usingbistrimethylsilyltrifluoroacetamide (BSTFA), followed by introducing adouble bond between the first and the second carbon atoms using2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as an oxidizing agent.

However, this process, in addition to the usage of expensive reagents,has extra problems in that the reaction should be carried out under anitrogen gas flow and with an anhydrous solvent due to BSTFA'ssensitivity to water, and excessive impurities may be produced due tothe use of a quinone as an oxidizing agent under reflux condition for 20hours in a solvent having a high boiling point, i.e., 1,4-dioxane.Further, substantial losses of the obtained product may occur during apurification step, and, therefore, it is not suitable for massproduction.

U.S. Pat. No. 5,091,534 and European Patent Nos. 428,366 and 473,225teach a process for preparing finasteride, which comprises silylatingthe compound of the above formula (III) in the presence of a base andintroducing a halogen such as iodine and bromine into the 2-position ofthe compound, followed by introducing a double bond between the firstand the second carbon atoms using a strong base such as potassiumtert-butoxide, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and1,5-diazabicyclo[4.3.0]non-5-ene (DBN).

However, this process also suffers from a poor purity (about 80%) sincethe reactants and products tend to be decomposed due to the high pH ofthe reaction solution containing the strong base, and a low yield afterseveral purification steps (about 30%).

A method for dehydrogenating a 3-oxo-4-azasteroid compound through asulfinate intermediate is disclosed in J. Med. Chem. 27(12): 1690(1984). First, as shown in Scheme 2, the compound of formula (VI) isreacted with dimethylsulfate to obtain the compound of formula (VII)having a protected amide. Next, the compound of formula (VII) is reactedwith diphenyldisulfide in the presence of a strong base such as lithiumdiisopropylamide (LDA) at −78° C. to produce the compound of formula(VIII) having a phenylsulfide group at the 2-position, and then theamide of the compound of formula (VIII) is deprotected in the presenceof a strong acid to obtain the compound of formula (IX). Finally, thecompound of formula (X) is prepared by using an oxidizing agent and thecompound of formula (XI) is obtained by refluxing the compound offormula (X) in toluene.

However, this method employs the unnecessary steps of protecting anddeprotecfing the amide group, consists of five complicated steps, anduses an inflammable diisopropylamide. Further, it is performed atextremely low temperature, i.e., −78° C., which is not practicallyapplicable to an industrial scale.

As discussed above, the conventional methods for preparing finasterideare disadvantageous in that they employ water-sensitive, expensive ortoxic reagents, require extreme reaction conditions or comprisecomplicated multiple steps, thereby rendering them unsuitable for massproduction. Especially, in most conventional methods, finasteride isprepared under a vigorous condition or in the presence of a strong basein a final step, resulting in excessive impurities.

There are strict provisions as to the impurities of finasteride. Forexample, according to the provision of European Pharmacopeia, the amountof individual impurity A, B and C identified below, may not exceed 0.3%and the total amount of the impurities should not exceed 0.6%.Similarly, according to U.S. Pharmacopeia, the amount of individualimpurity A, B and C should not exceed 0.5% and the total amount thereofshould not exceed 1.0%.

Impurity A has a structure that the double bond of finasteride issaturated, impurity B has a methylester group at the 17β position,instead of the tert-butylamino group of finasteride, and impurity Ccontains an extra double bond between the fifth and the sixth carbonatoms.

Further, finasteride cannot be easily purified using a conventionalmethod such as recrystallization when it is mixed with an excessiveamount of the above impurities A to C, since finasteride and impuritiesA to C have similar structures. In particular, during therecrystallization of finasteride to meet the amount of impurity A below0.3%, loss of yield is inevitably caused, thus it renders the finalyield of finasteride only 30 to 40%. Further, impurities A and C cannotbe easily removed even using column chromatography. Accordingly, therehas been a need to develop a method for preparing highly pure1-androstene derivatives including finasteride.

SUMMARY OF THE INVENTION

It is a primary object of the present invention to provide a method forpreparing highly pure 1-androstene derivatives under the mild conditionswithout using a strong base in a final step.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with one aspect of the present invention, a method forpreparing a 1-androstene derivative of formula (I)

comprises reacting a 2-iodo-androstane derivative of formula (XII)

with an oxidizing agent, wherein R is —OH, —OR¹ or —NHR², in which R¹ isa straight or branched C₁₋₅ alkyl group and R² is a straight or branchedC₁₋₅ alkyl group or 2,5-bis(trifluoromethyl)phenyl group.

In the present invention, 1-androstene derivative of formula (I) isprepared by reacting 2-iodo-androstane derivative of formula (XII) withan oxidizing agent to oxidize an iodo group thereof into an iodoxygroup, which is easily removed during the reaction, as shown in Scheme3.

In accordance with the simple method of the present invention,1-androstene derivatives can be produced in a high purity and yieldunder mild conditions.

The derivative of formula (XII) used as a starting material of thepresent invention can be prepared by a conventional method disclosed inEuropean Patent No. 473,225, which comprises reacting an androstanecompound, e.g., formula (XIII) with a silylating agent in the presenceof a base, followed by reacting with iodine to obtain the derivative offormula (XII),

whereinR is —OH, —OR¹ or —NHR², in which R¹ is a straight or branched C₁₋₅alkyl group and R² is a straight or branched C₁₋₅ alkyl group or2,5-bis(trifluoromethyl)phenyl group.

In the present invention, the compound of formula (XIIIa) correspondingto the compound of formula (XIII) wherein R is tert-butylamino may beprepared by a method shown in Scheme 4 (see Korean Patent ApplicationNo. 2003-20671).

The oxidizing agent which may be used in the present invention includesm-chloroperbenzoic acid, peracetic acid, trifluoroperacetic acid,permaleic acid, sodium bromite, sodium hypochloride, hydrogen peroxide,iodosomethylbenzene and iodosobenzene; and m-chloroperbenzoic acid ismost preferred.

In a preferred embodiment of the present invention, the oxidizing agentmay be employed in an amount ranging from 2.0 to 6.0 equivalents,preferably 3.0 to 4.0 equivalents based on 1.0 equivalent of thederivative of formula (XII).

In the present invention, the total amount of the oxidizing agent may beadded at a time during an early step of the reaction, or in dividedamounts, e.g., ranging from ¼ to ½ of the total amount, at intervals of30 to 60 minutes.

The organic solvent which may be used in the present invention includesat least one solvent selected from the group consisting oftetrahydrofuran, dioxane, acetonitrile, dimethylacetamide,dimethylformamide and dimethylsulfoxide; and tetrahydrofuiran is mostpreferred.

The method of the present invention can be accomplished by using theoxidizing agent alone. However, if free acids produced during thereaction, i.e., m-chlorobenzoic acid and iodic acid whenm-chloroperbenzoic acid is used as an oxidizing agent, remain in thereactant mixture without any neutralizing step, the pH of the reactionsolution may decrease, and thus the reactants, products and reagents maydecompose, thereby producing undesired by-products. On the other hand,if the reaction is conducted at a pH in the range of 5.5 to 7.5, thereaction can be completed with substantially less by-products.

The reaction of the present invention may be carried out at atemperature in the range of 0 to 50° C., preferably 15 to 30° C.

Although the time period for completing the present reaction may varywith the reaction temperature or the amount of the oxidizing agent used,about 8 to 24 hours may be sufficient.

Thus, in accordance with the simple method of the present invention,1-androstene derivatives can be produced with high purity and yield over80% under mild conditions. Further, the method of the present inventionemploys short reaction steps, and, therefore, is suitable for massproduction.

The present invention will be described in further detail with referenceto Examples. However, it should be understood that the present inventionis not restricted by the specific Examples.

PREPARATION EXAMPLE 1 Preparation of benzothiazolyl3-oxo-4-aza-5α-androstane-17β-thiocarboxylate

200 g of 3-oxo-4-aza-5α-androstane-17β-carboxylic acid and 250 g ofbisbenzothiazolylthioester (bis-BTS) were mixed in 3 l ofmethylenechloride, and stirred at room temperature for 30 minutes. 197 gof triphenylphosphine was added thereto, stirred for 30 minutes and 105ml of triethylamine diluted with 200 ml of methylenechloride was addeddropwise thereto over a period of 30 minutes, followed by stirring themixture at room temperature for 4 hours. The precipitation formed wasfiltered, washed successively with methylenechloride and diethylether,and dried at 40° C. overnight to obtain 281 g of the title compound(yield: 96%) as a pale white solid.

m.p.: 245˜247° C.; ¹H-NMR (300 MHz, CDCl₃, δ); 8.02 (d, 1H), 7.91 (d,1H), 7.50 (m, 2H), 5.54 (brs, 1H), 3.06 (dd, 1H), 2.76 (t, 1H), 2.45 (m,2H), 2.26 (m, 2H), 1.9 (m, 2H), 1.75 (m, 2H), 1.65 (m, 1H), 1.51˜1.34(m, 7H), 1.21 (m, 1H), 1.12 (m, 1H), 0.91 (s, 3H), 0.81 (m, 1H), 0.79(s, 3H)

PREPARATION EXAMPLE 2 Preparation ofN-(tert-butyl)-3-oxo-4-aza-5α-androstane-17β-carboxamide (compound offormula (XIIIa))

281 g of benzothiazolyl 3-oxo-4-aza-5α-androstane-17β-thiocarboxylateobtained in Preparation Example 1 was added to 2.81 of dimethylformamideand 315 ml of tert-butylamine was added thereto, followed by stirringthe mixture at 50° C. for 4 hours. The resultant was cooled to about 10°C., 5.6 l of water was slowly added thereto and stirred at roomtemperature for an hour. The precipitation formed was filtered, washedsuccessively with water and isopropylether, and dried at 40° C.overnight to obtain 206 g of the title compound (yield: 92%) as a palewhite solid.

m.p.: 280˜284° C.; ¹H-NMR (300 MHz, CDCl₃, δ); 5.66 (brs, 1H), 5.07(brs, 1H), 3.07 (dd, 1H), 2.41, (m, 2H), 2.12 (m, 2H), 2.10˜1.80 (m,3H), 1.8˜1.52 (m, 4H), 1.51˜1.41 (m, 4H), 1.35 (s, 9H), 1.3˜1.18 (m,2H), 1.15˜0.92 (m, 2H), 0.91 (s, 3H), 0.90˜0.70 (m, 1H), 0.69 (s, 3H)

PREPARATION EXAMPLE 3 Preparation ofN-(tert-butyl)-2-iodo-3-oxo-4-aza-5α-androstane-17β-carboxamide(compound of formula (XII) wherein R is tert-butylamino)

205 g of N-(tert-butyl)-3-oxo-4-aza-5α-androstane-17β-carboxamideobtained in Preparation Example 2 and 248 ml oftetramethylethylenediamine were added to 2 l of toluene, cooled to 0°C., 138 ml of trimethylchlorosilane was added dropwise thereto, andstirred for 30 minutes. 208 g of iodine was added thereto in 1/4portions every 30 minute over a period of 2 hours, followed by stirringthe mixture for 2 hours. 2 l of 10% sodium thiosulfate was addeddropwise to the mixture and stirred overnight. The precipitation formedwas filtered, washed successively with water and isopropylether, anddried at 40° C. overnight to obtain 255 g of the title compound (yield:93%) as an white solid.

m.p.: 218˜220° C.; ¹H-NMR (300 MHz, CDCl₃, δ); 5.82 (brs, 1H), 5.06(brs, 1H), 4.75 (dd, 1H), 3.15 (dd, 1H), 2.56 (dd, 1H), 2.20˜1.88 (m,4H), 1.80˜1.36 (m, 8H), 1.34 (s, 9H), 1.32˜1.12 (m, 2H), 1.10˜0.90 (m,2H), 0.88 (s, 3H), 0.85 (m, 1H), 0.67 (s, 3H)

EXAMPLE 1 Preparation ofN-(tert-butyl)-3-oxo-4-aza-5α-androstene-17β-carboxamide (finasteride:compound of formula (II))

244 g of N-(tert-butyl)-2-iodo-3-oxo-4-aza-5α-androstane-17β-carboxamideobtained in Preparation Example 3 was added to a mixture of 2.4 l oftetrahydrofuran and 1.4 l of saturated sodium bicarbonate. 112 g ofm-chloroperbenzoic acid (content: maximum 75%) was added thereto in 1/4portions every 1 hour, followed by stirring the mixture overnight. Aftercompletion of the reaction, pH of the mixture was adjusted to about 7using saturated sodium bicarbonate, followed by stirring the mixture foran hour. The precipitation formed was filtered and the crude product wasdissolved in 1.5 l of methylenechloride, washed successively with 1.5 lof 10% sodium sulfite (2 times) and 1.5 l of water. The isolatedmethylenechloride layer was dried, filtered and the solvent wasevaporated off. The resulting residue was refluxed in 435 ml ofisopropylacetate for an hour, cooled to room temperature, filtered andwashed with ether. The precipitate formed was dispersed in a mixture of2.25 l of water and 250 ml of acetic acid, stirred at 50° C. for 2hours, cooled to room temperature, filtered and washed with water. Then,the precipitation was dried at 40° C. overnight to obtain 148.6 g of thetitle compound (yield: 82%) as an white solid.

m.p.: 257˜259° C.; purity: 99.8% (HPLC); impurity A: 0.07%, impurity B:0%, impurity C: 0.05%;

¹H-NMR (300 MHz, ¹H-NMR CDCl₃) δ6.82(d, 1H), 5.81(d, 1H), 5.49(brs, 1H),5.10(brs, 1H), 3.34(dd, 1H), 2.21(t, 1H), 2.01(m, 2H), 1.80˜1.60(m, 7H),1.34(s, 9H), 1.50-1.26(m, 5H), 1.07-1.00(m, 3H), 0.98(s, 3H), 0.71(s,3H)

EXAMPLE 2 Preparation ofN-(tert-butyl)-3-oxo-4-aza-5α-androstene-17β-carboxamide (finasteride:compound of formula (II))

244 g of N-(tert-butyl)-2-iodo-3-oxo-4-aza-5α-androstane-17β-carboxamideobtained in Preparation Example 3 was added to a mixture of 2.0 l oftetrahydrofuran and 2.0 l of saturated sodium bicarbonate. 141 g ofm-chloroperbenzoic acid (content: maximum 75%) was added thereto in 1/3portions every 1 hour, followed by stirring the mixture overnight.Thereafter, 145.2 g of the title compound (yield: 80%) was obtained as awhite solid in accordance with Example 1.

Purity: 99.7% (HPLC); impurity A: 0.09%, impurity B: 0%, impurity C:0.07%;

¹H-NMR data was the same as Example 1

COMPARATIVE EXAMPLE 1 Preparation ofN-(tert-butyl)-3-oxo-4-aza-5α-androstene-17β-carboxamide (finasteride:compound of formula (II)) without maintaining pH of the reactantsolution in the range of 5.5 to 7.5

244 g of N-(tert-butyl)-2-iodo-3-oxo-4-aza-5α-androstane-17β-carboxamideobtained in Preparation Example 3 was dissolved in 2.4 l oftetrahydrofuran. 141 g of m-chloroperbenzoic acid (maximum content: 75%)was added thereto in 1/3 portions every 1 hour, followed by monitoringthe process of the reaction using thin layer chromatography (TLC). Thecolor of the reactant solution gradually became dark black, pH thereofwas drop to below 4, and a large 30 amount of undesired impurities wereproduced. The reaction was terminated at hour 6 when the reaction wasnot yet completed. Thereafter, 136.1 g of the crude title compound(yield: 75%) was obtained as a yellow solid in accordance with Example1.

Purity: 52.7% (HPLC); impurities: unreacted compound obtained inPreparation Example 3=4.6%, unidentified compound=39.2%, impurityA=2.8%, impurity B=0%, impurity C=0.65%

COMPARATIVE EXAMPLE 2 Preparation ofN-(tert-butyl)-3-oxo-4-aza-5α-androstene-17β-carboxamide (finasteride:compound of formula (II)) in accordance with the prior method disclosedin European Patent Nos. 428,366 and 473,225

8.0 g of potassium t-butoxide was dispersed in 20 ml ofN,N-dimethylformamide (DMF), cooled to −10° C. and 3.5 g ofN-(t-butyl)-2-iodo-3-oxo-4-aza-5α-androstene-17β-carboxamide dissolvedin 15 ml of DMF was added dropwise thereto while maintaining the sametemperature. The mixture was stirred vigorously for 10 minutes and thereaction was quenched by the dropwise addition of 7.2 ml of acetic acidwhile maintaining the reaction temperature of below 10° C. Afterstirring the mixture for 5 minutes, 200 ml of 20% sodium chloride wasslowly added thereto at 0° C. The resulting solution was stirredovernight at 0° C., filtered, washed and dried under a vacuum at 60° C.The crude product (HPLC purity: 75%) was refluxed in 20 ml ofisopropylacetate for an hour, cooled, filtered and washed with ether.The precipitate formed was dispersed in the mixture of 45 ml of waterand 5 ml of acetic acid, stirred at 50° C. for 2 hours, cooled to roomtemperature, filtered and washed with water. Then, the precipitate wasdried at 40° C. overnight to obtain 0.96 g of the title compound (yield:37%) as an white solid.

m.p.: 256˜159° C.; purity: 98.1% (HPLC); impurity A=0.9%, impurity B=0%,impurity C=0.45%; ¹H-NMR data was the same as Example 1

While the invention has been described with respect to the abovespecific embodiments, it should be recognized that various modificationsand changes may be made to the invention by those skilled in the artwhich also fall within the scope of the invention as defined by theappended claims.

1. A method for preparing a 1-androstene derivative of formula (I)

which comprises reacting a 2-iodo-androstane derivative of formula (XII)

with an oxidizing agent, wherein R is —OH, —OR¹ or —NHR², in which R¹ isa straight or branched C₁₋₅ alkyl group and R² is a straight or branchedC₁₋₅ alkyl group or 2,5-bis(trifluoromethyl)phenyl group.
 2. The methodof claim 1, wherein the oxidizing agent is selected from the groupconsisting of m-chloroperbenzoic acid, peracetic acid,trifluoroperacetic acid, permaleic acid, sodium bromite, sodiumhypochloride, hydrogen peroxide, iodosomethylbenzene and iodosobenzene.3. The method of claim 1 or 2, wherein the oxidizing agent ism-chloroperbenzoic acid.
 4. The method of claim 1, wherein the oxidizingagent is employed in an amount ranging from 2.0 to 6.0 equivalents basedon 1.0 equivalent of the derivative of formula (XII).
 5. The method ofclaim 1, wherein the reaction is conducted at a pH ranging from 5.5 to7.5.
 6. The method of claim 1, wherein R is tert-butylamino or2,5-bis(trifluoromethyl)phenylamino.